Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice.
Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice.
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DOI：
10.1371/journal.pone.0160431
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Vachharajani V
中科院分区：
文献类型：
--
作者：
Wang X;Buechler NL;Martin A;Wells J;Yoza B;McCall CE;Vachharajani V
肥胖会增加脓毒症患者的发病率和资源利用率。脓毒症从早期/高炎症阶段过渡到晚期/低炎症阶段。大多数败血症--死亡发生在晚期败血症；目前尚无治疗晚期败血症的方法。在瘦小鼠身上，我们已经证明sirtuins(SIRT)调节这种转变。在这里，我们研究了sirtuins，特别是脂肪组织中丰富的SIRT-2在肥胖症合并脓毒症从早期到晚期脓毒症转变过程中的作用。采用盲肠结扎穿刺术(CLP)诱导ob/ob小鼠脓毒症。我们测量了不同时间点的微血管炎症对脂多糖/生理盐水再刺激的反应，作为免疫功能的标志，以跟踪ob/ob小鼠的脓毒症阶段。我们检测了SIRT-2在脓毒症不同阶段的表达。我们研究了在低炎性阶段抑制SIRT-2对免疫功能和7天存活期的影响。我们使用RAW264.7(原始)脓毒症细胞模型进行机制研究。我们证实了饮食诱导肥胖(DIO)小鼠脓毒症的关键发现。我们观察到，与WT小鼠相比，肥胖/肥胖脓毒症小鼠的早期炎症反应增强，持续和延长的低炎症期。与显示SIRT1表达增加的WT小鼠不同，我们发现ob/ob小鼠在炎症减退期间SIRT2水平增加。在脓毒症的低炎性阶段，在ob/ob小鼠体内抑制sirt-2通过激活内皮细胞和循环白细胞逆转了体内被抑制的微血管炎症，并显着提高了存活率。我们在DIO-脓毒症小鼠的这个项目中证实了SIRT2在脓毒症低炎性阶段的作用这一关键发现。从机制上讲，在脓毒症细胞模型中，sirt-2的表达通过去乙酰化NFκBp65来调节炎症反应。Sirt-2调节患有脓毒症的肥胖小鼠的微血管炎症，可能为肥胖并发脓毒症提供一个新的治疗靶点。
Obesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins (SIRTs) modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis. Sepsis was induced using cecal ligation and puncture (CLP) in ob/ob mice. We measured microvascular inflammation in response to lipopolysaccharide/normal saline re-stimulation as a “second-hit” (marker of immune function) at different time points to track phases of sepsis in ob/ob mice. We determined SIRT-2 expression during different phases of sepsis. We studied the effect of SIRT-2 inhibition during the hypo-inflammatory phase on immune function and 7-day survival. We used a RAW264.7 (RAW) cell model of sepsis for mechanistic studies. We confirmed key findings in diet induced obese (DIO) mice with sepsis. We observed that the ob/ob-septic mice showed an enhanced early inflammation and a persistent and prolonged hypo-inflammatory phase when compared to WT mice. Unlike WT mice that showed increased SIRT1 expression, we found that SIRT2 levels were increased in ob/ob mice during hypo-inflammation. SIRT-2 inhibition in ob/ob mice during the hypo-inflammatory phase of sepsis reversed the repressed microvascular inflammation in vivo via activation of endothelial cells and circulating leukocytes and significantly improved survival. We confirmed the key finding of the role of SIRT2 during hypo-inflammatory phase of sepsis in this project in DIO-sepsis mice. Mechanistically, in the sepsis cell model, SIRT-2 expression modulated inflammatory response by deacetylation of NFκBp65. SIRT-2 regulates microvascular inflammation in obese mice with sepsis and may provide a novel treatment target for obesity with sepsis.